IngredientsPhlorotannins are a unique set of polymers synthesized by brown algae (Phaeophyta), which are structurally analogous to tannins from terrestrial plants. They are a group of complex polymers of phloroglucinol (1,3,5-trihydroxybenzene), which are unique compounds from marine brown algae. Among the algal polyphenols, phlorotannins are unique to brown seaweeds and have immense value as potent modulators of biochemical processes linked to chronic diseases.
Phlorotannins are highly hydrophilic in nature, with molecular weights ranging from 126 Da to 650 kDa, and are comprised of polymeric chains of base phloroglucinol (1,3,5-trihydroxybenzene) residues connected via C–C and/or C–O–C couplings. They are produced via the polymerization of the phloroglucinol molecule (benzene-1,3,5-triol) through the polyketide pathway reaction and stored in physodes and/or cell-wall-forming complexes.
Phlorotannins are a group of phenolic secondary metabolites isolated from a variety of brown algal species belonging to the Fucaceae, Sargassaceae, and Alariaceae families. Reported phlorotannin-bearing species include Ishige okamurae, Ecklonia cava, E. kurome, E. stolonifera, Pelvetia siliquosa, Eisenia arborea, and E. bicyclis, as well as species in the genera Cystophora and Fucus. They have been widely identified in Ecklonia, Eisenia, and Ishige species.
Phlorotannins have been found so far in all studied brown algae (Ochrophyta, Phaeophyceae), and their content in algal tissues varies from 0.5 to 30% dry weight. This characteristic is species-specific, with the maximum phlorotannin level reported from representatives of the orders Fucales and Dictyotales. Phlorotannins constitute an important class of polyphenolic compounds in marine brown algae accounting for about 5–12% of their dry weight.
The content of phlorotannins in seaweeds depends on environmental conditions, such as tides, salinity, light availability, UV radiation, and herbivory intensity. Besides inter-species differences, phlorotannin content in algal cells correlates with water salinity, nutrient availability, plant size, and developmental stage.
The exact biological roles of phlorotannins in seaweeds have not been fully elucidated; however, they are believed to play an important role in cell wall structure, UV protection, and as a possible defense mechanism against marine herbivory. Marine polyphenols are unique algae metabolites not found in land plants. These phenolic compounds are structural components of the algal cell wall and protect them from adverse physical and chemical environmental factors.
Phlorotannins are classified into six different classes according to the variations of their assembly and distribution of hydroxyl groups: eckols, fuhalols, fucophlorethols, phlorethols, fucols, and carmalols. Phlorethols and fuhalols present aryl-ether linkages; fucols aryl-aryl bonds; and fucophlorethols a mixture of ether and phenyl bonds. Eckols present a 1,4-dibenzodioxin unit. Carmalols present a 4-dibenzodioxin unit at the third and seventh position.
This linkage polymorphism together with positional isomerism gives rise to a great structural diversity of phlorotannins. Due to the presence of highly complex polymeric mixtures of structural and conformational isomers of phlorotannins and the absence of available commercial phlorotannin standards, accurate chemical identification from extracts using MS/MS is difficult.
Phlorotannins are available in several commercial and research forms:
Fucales are an order within the Phaeophyceae that include most of the common littoral seaweeds in temperate and subtropical coastal regions. Many species of this order have long been a part of human culture with applications as food, feed, and medicine.
Traditional Chinese medicine used hot water extracts of several types of seaweed in the treatment of cancer. Additionally, the Japanese and Chinese cultures used seaweed to treat goiter and other glandular problems as long ago as 300 BC. The Romans used seaweed in the treatment of wounds, burns, and rashes.
Fucus vesiculosus is a good source of iodine, an essential component of thyroid hormones, and has been used in traditional medicine for the treatment of thyroid dysfunction, including goiter and obesity. Sargassum species have been used for centuries in agriculture as fertilizers, although their applications may go beyond fertilization purposes; they have shown particularly interesting properties for the development of plant-biostimulation strategies and/or abiotic-stress mitigation.
Since the time phlorotannins were discovered in the 1970s, they have been suggested as a main factor responsible for the antimicrobial activities attributed to algae extracts.
It should be noted that while brown seaweeds themselves have extensive historical use across multiple cultures, the specific identification and isolation of phlorotannins as distinct bioactive compounds is a modern scientific achievement. The historical uses attributed to phlorotannin-rich species refer to the whole-plant preparations rather than to isolated phlorotannins, and should be understood in that context.
Several individual phlorotannin compounds have been isolated and characterized as particularly bioactive:
In the same way as the tannins of terrestrial plants, phlorotannins are highly soluble in water, strongly bind to proteins, polysaccharides, and other biopolymers, chelate divalent metals, and have a polymer structure. These properties underlie their radical-scavenging capacity. The crude extract of F. vesiculosus and its ethyl acetate fraction showed good radical scavenging activity, particularly towards nitric oxide (NO•).
Phlorotannin subfractions of F. vesiculosus with different molecular weights were shown to inhibit lipopolysaccharide-induced NO• production in macrophages, with stronger effects being observed for fractions of lower molecular weights. Of three intracellular markers analyzed, inducible NO• synthase showed the highest sensitivity to almost all phlorotannin-rich samples, followed by interleukin-1β and cyclooxygenase-2.
Three phlorotannins from Ecklonia cava were found to inhibit TNF-α, IL-1β, and PGE₂ production at the protein level. These results showed that the anti-inflammatory properties of these compounds are related to the downregulation of proinflammatory enzymes, iNOS and COX-2, through the negative regulation of the NF-κB pathway in Aβ₂₅₋₃₅-stimulated cells.
The NF-κB signaling system is a potential target for creating innovative targeted drugs based on brown algae phlorotannins. Ecklonia cava inhibits the gene expression of MUC5AC mucin in human airway epithelial cells and fine dust-induced inflammation and oxidative stress by downregulation of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α.
Enzymatic assays of Fucus vesiculosus extracts revealed promising inhibition against enzymes such as α-glucosidase, α-amylase, and pancreatic lipase, indicating their potential in combating metabolic disorders such as diabetes and obesity.
Studies on the hypnotic effects of phlorotannins have shown their characteristics as agonists for gamma-aminobutyric acid type A (GABAA)-benzodiazepine (BZD) receptors.
Phlorotannin supplementation significantly improved scopolamine-induced memory impairment and restored synaptic protein expression (synaptophysin, synapsin-1, and postsynaptic density protein-95) in the hippocampus. Additionally, phlorotannins enhanced brain-derived neurotrophic factor (BDNF) signaling and activated the extracellular signal-regulated kinase/cAMP response element-binding protein (ERK-CREB) pathway, essential for synaptic plasticity.
In addition to NF-κB, many other signaling pathways involved in the pathogenesis of chronic neurodegenerative diseases can become targets for algal phlorotannins. Furthermore, some studies have presented mechanisms of the neuroprotective action of these compounds, confirming that they can be considered candidates for nutraceuticals and as future drugs for the treatment of neuroinflammation in neurodegenerative diseases.
Phlorotannins from brown seaweeds show antifungal activity against dermal and plant fungi, and larvicidal activity against mosquitos and marine invertebrate larvae. The lowest minimum inhibitory concentration (MIC) values against bacteria (16–32 μg/mL) were reported for fucofuroeckol-A from E. bicyclis.
Evidence level: Strong in vitro; limited human data.
Purified phlorotannins from brown algae have antioxidant, antitumor, anticancer, anti-inflammatory, antiviral, antimicrobial, antifungal, and larvicidal activities. Most antioxidant evidence is from cell-free assays (DPPH, ABTS, FRAP) and cell-culture models. Human evidence is limited, but one randomized controlled trial exists: Eighty subjects were randomly assigned to receive either a placebo or Ecklonia cava extract (Seapolynol, 360 mg/day) for 12 weeks. In response to Seapolynol consumption, body fat was significantly reduced from the baseline value. The trial also assessed oxidative and inflammatory stress markers.
Bioactivity studies have identified neuroprotective, antidiabetic, anticancer, antioxidant, anti-inflammatory, antimicrobial, and microbiome-beneficial properties, highlighting the multi-faceted potential of phlorotannins. Overall, the majority of such findings have been generated via biochemical and cell-based assays, with only a limited number of in vivo animal experiments conducted.
Evidence level: Robust in vitro and animal evidence; early-stage human data.
Multiple in vitro and animal studies document inhibition of NF-κB, COX-2, iNOS, and pro-inflammatory cytokines. Purified extracts from Fucus spp. exhibited high radical scavenging activity in a dose-dependent manner, and showed significant inhibition against lipoxygenases, which are enzymes involved in synthesizing mediators for progression of inflammation-related diseases.
A human clinical trial on respiratory symptoms was recently conducted: EC inhibits the gene expression of MUC5AC mucin in human airway epithelial cells, fine dust-induced inflammation, and oxidative stress by downregulation of IL-1β, IL-6, and TNF-α. However, no clinical studies had previously examined the efficacy of EC on respiratory symptoms, including cough, sputum, and dyspnea.
Evidence level: Promising but limited; small human trials, mostly short-term.
Metabolomic studies and clinical trials are scarce, and thus many phlorotannin health-beneficial effects in humans are not yet confirmed.
One randomized controlled trial in prediabetic patients provides direct human evidence: A double-blind, randomized controlled trial was conducted in 20 prediabetic patients with no other health complications. Subjects were given 600 mg of seaweed extract in a single dose for acute effect investigation. Postprandial blood glucose (PPBG) and postprandial insulin levels (PPIL) were measured at intervals of 30, 60, 90, and 120 minutes following 75 g of carbohydrate consumption. Insignificant differences were shown for PPBG levels between study groups at intervals of 30 and 60 min; however, PPBG results were significantly lower in the intervention group compared to placebo at 90 and 120 minutes after carbohydrate consumption.
Phlorotannins isolated from F. vesiculosus and A. nodosum had no side effects in 23 participants (12 women and 11 men) following treatment at 250 mg/capsule. They decreased incremental areas under the curve (IAUC) in plasma insulin, post-load plasma insulin concentration, plasma glucose areas under the curve (AUC), and postprandial insulin concentration. Interestingly, phlorotannins from F. vesiculosus and A. nodosum elevated the level of a surrogate marker for insulin sensitivity.
A Phase IIa trial has also been registered: A multi-center, randomized, double-blind, placebo-controlled, parallel-design, 12-week, therapeutic exploratory study involving patients with type 2 diabetes mellitus and recent cardiovascular complications was designed. After screening, 114 patients were stratified and randomized in a 1:1:1 ratio to three arms: PH100 800 mg/day, PH100 1600 mg/day, or placebo.
Although considerable research showing the antidiabetic and anticancer potential of phlorotannins is now available, further clinical trials are still necessary to conclusively demonstrate the efficacy of these compounds as adjuvants for diabetes and cancer prevention or treatment.
Evidence level: Preliminary; small human pilot studies only.
Several small human pilot trials have evaluated effects on blood lipids in individuals with hypercholesterolemia, cited in the literature with Ecklonia cava polyphenol preparations. Phlorotannins have received significant attention in medicine due to their bioactive activities such as antioxidant, anticoagulant, antithrombotic, antidiabetic, enzymatic regulatory, antimicrobial, antitumoral, anti-inflammatory, antihypertensive, and antiviral activities. These are largely in vitro or small pilot study findings; large, well-powered RCTs in cardiovascular end points have not been published.
Evidence level: Mechanistically novel; animal model and early human evidence; regulatory recognition in South Korea.
It has been demonstrated that phlorotannins from brown seaweeds have hypnotic effects in in vitro and in vivo studies as well as in clinical trials. Phlorotannins exert sedative-hypnotic effects via the gamma-aminobutyric acid type A-benzodiazepine receptor. The brown seaweed Ecklonia cava supplement containing phlorotannins has been approved by the Ministry of Food and Drug Safety (South Korea) as a health-functional ingredient that helps improve sleep quality.
Phlorotannin supplements from Ecklonia cava have been approved by the Ministry of Food and Drug Safety in South Korea as functional ingredients for improving sleep quality.
Evidence level: Preclinical (animal and cell culture) only; no confirmed human clinical trials at this time.
Eckmaxol, a phlorotannin from E. maxima, possesses protective activity against amyloid-beta (Aβ) oligomer-induced neurotoxicity in SH-SY5Y cells in vitro. Results from a neuroinflammation study indicated that dieckol from E. cava might be applied as a drug candidate for the development of new generation therapeutic agents against Alzheimer's disease.
Phlorotannins have shown promising results in the treatment of Alzheimer's and Parkinson's disease and arthritis. However, these findings are from preclinical models. Additional material is required to further investigate the functions of these compounds in mammalian systems for the development of phlorotannins as new pharmacological probes or potential drug leads for treating Alzheimer's disease.
Evidence level: In vitro and animal models only; no human clinical trials established.
Numerous studies have demonstrated the anticarcinogenic activity of polyphenolic algae compounds both in cell culture and experimental animal models. Although clinical studies are still needed to support this evidence, phlorotannins and bromophenols constitute an emerging bioactive group with high potential as chemopreventive agents and/or potential adjuvants for existing cancer therapies.
Evidence level: In vitro and some in vivo evidence; no human clinical trials.
Phlorotannins are secondary metabolites produced by brown seaweeds with antiviral, antibacterial, antifungal, and larvicidal activities. Further studies of the biological activity of phlorotannins against fungal and parasitic infections in aquaculture fish, livestock, and companion animals are needed for systematic analyses of their effectiveness.
Evidence level: Modest; one double-blind RCT reported significant effects on body fat.
Eighty subjects were randomly assigned to receive either a placebo or Ecklonia cava extract (Seapolynol, 360 mg/day) for 12 weeks. In response to Seapolynol consumption, body fat was significantly reduced from the baseline value. The study also documented effects on oxidative and inflammatory stress. This is a single trial and requires replication in larger, more diverse populations.
Studies over the past decades have implicated phlorotannins with several bioactivities, including anti-herbivory, antioxidants, anti-inflammatory, anti-microbial, anti-proliferative, anti-diabetic, radio-protective, adipogenic, anti-allergic, and anti-human immunodeficiency virus (anti-HIV) properties.
The body systems with which phlorotannins are most extensively associated in the published literature include:
The following dosages appear in the published clinical or regulatory literature and are reported only as stated in those sources:
Studies have shown that phlorotannins from brown seaweeds showed low toxicity in cell lines, microalgae, seaweed spores, plants, invertebrates, animals (fish, mice, rats, and dogs) and humans at a moderate dosage. Mild side-effects were recorded in humans, fish, and dogs.
The EFSA Panel noted that there is no evidence of genotoxicity for the novel food (Ecklonia cava phlorotannins). A subchronic repeated dose oral toxicity study in rodents tested the novel food at daily doses of 0, 375, 750, and 1,500 mg/kg body weight. The Panel considered the mid-dose as the NOAEL of the study. Taking into account this NOAEL of 750 mg/kg bw per day and by applying an uncertainty factor of 200, the Panel considered an intake level of 3.75 mg/kg bw per day as safe.
From the few toxicity and safety studies available, phlorotannins, especially dieckol, are safe, and any possible adverse effects are extremely mild.
Most studies on the safety and toxicity of phlorotannins in cell lines focused only on eckols and dieckol. The other subclasses of phlorotannins, such as fuhalols, phlorethols, fucols, and fucophloroethols, have not been tested. There are sparsely available studies on the relative safety profile of phlorotannins in humans.
The biological activity of phlorotannins is limited mainly by their lack of solubility and permeability, as well as their extensive biotransformation by the gut microbiota, which determines their degree of absorption in the human gastrointestinal tract. Therefore, the effectiveness of phlorotannins is determined by their bioaccessibility and bioavailability, since they need to be properly digested and absorbed in order to access the bloodstream and then reach the appropriate target location.
Phlorotannins are unstable in the acidic condition of the gut and the alkaline condition of the small intestine; if not protected, they could easily be transformed and/or metabolized. Phlorotannins are water-soluble, but their absorption in the human GI tract following consumption could be low, as evidence suggested that phlorotannins were mainly absorbed after being metabolized in the large intestine, not in the stomach and the small intestine.
Despite extensive research on the biological activities of eckols, little is known about their absorption, distribution, metabolism, and excretion (ADME) properties. This gap limits the ability to develop optimal dosing strategies, assess bioavailability, and predict human pharmacokinetics—critical elements in advancing these compounds from preclinical research to clinical applications.
Molecular analyses have indicated that phlorotannins show interactions with various cytochrome P450 (CYP) isoforms. This information is vital for predicting potential drug-drug interactions and guiding dosage adjustments in co-administration scenarios. The clinical significance of these CYP interactions in humans has not been established in formal interaction studies.
Based on the existing studies of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) characteristics of phlorotannin compounds, investigators have examined the bioavailability of the phlorotannin ligand molecules as oral drug candidates. Following first-pass metabolism, polarity, aqueous solubility, and permeability of the gut-blood barrier appeared at an adequate level compared with standard drugs.
Because phlorotannins may modulate α-glucosidase and α-amylase, and have demonstrated postprandial blood glucose-lowering effects in human subjects, theoretically they could have additive effects with antidiabetic medications; however, this interaction has not been formally studied in clinical settings as of available literature.
The EFSA Panel on Dietetic Products, Nutrition and Allergies was asked to deliver a scientific opinion on the safety of Ecklonia cava phlorotannins (marketed as SeaPolynolâ„¢) as a novel food. The novel food is a phlorotannin-rich alcohol extract of Ecklonia cava, which is an edible marine brown alga species. The intention is to market the novel food as a food supplement for healthy individuals over the age of 12 years. No specific safety data for children under 12, pregnant women, or lactating women was assessed in the EFSA opinion.
The application of biotechnological treatments using enzymes (e.g., fungal and bacterial glycosidases) and bacteria (e.g., probiotics, which are able to modulate gut microbiota) could be an exciting strategy to induce changes in phlorotannins' structure, which may considerably enhance their uptake into the blood, hence their bioavailability.
Phlorotannins have been widely studied through in vitro assays, in vivo models, and some clinical trials, which have shed light into a possible structure-function relation; however, metabolomic studies addressing their biotransformation and conjugation in the body, and thus their effective bioavailability, are still scarce.
A range of phlorotannins have been ascribed bioactivity and potential use as nutraceuticals and supplements, including trials of phlorotannin-rich extracts used as nutritional supplements in livestock feed to improve overall growth and condition. As of the current literature, the human evidence base remains modest. Most bioactivity findings derive from cell-based or animal studies. The most developed areas of human evidence include antidiabetic/insulin-sensitizing effects and sleep quality improvement. The anticancer and neuroprotective areas, while mechanistically compelling, remain at the preclinical stage. Further clinical trials are still necessary to conclusively demonstrate the efficacy of these compounds as adjuvants for diabetes and cancer prevention or treatment.
Health conditions that Phlorotannins may help support.
Body systems that Phlorotannins may help support.
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